This program project grant is in response to RFA-CA-08-020 entitled Tumor Stem Cells in Cancer Biology, Prevention, and Therapy. Recent evidence suggests that cancers have a cellular hierarchy in which a minority population of cancer cells, called cancer stem cells, drives the growth and spread of a tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the identification of pathways that regulate their growth, metastasis and survival in patients. Targeting the pathways involved in essential processes such as self renewal may lead to more effective therapies. This proposal is an interlocking set of projects designed to identify new cancer stem cell therapeutic targets against breast cancer and leukemia stem cells and to test drugs against some of these targets in a preclinical cancer stem cell model. The three projects of our Program are listed below. Project 1: Identification of self-renewal pathways in breast cancer stem cells and development of therapeutic pharmacological interventions. PI Mike Clarke, Stanford University. Project 2: Therapeutic targeting of CD47 on human leukemia and other cancer stem cells PI, Irv Weissman, Stanford University. Project 3: Microfluidic techniques for the molecular and functional analysis of gene expression, chromatin structure and in vitro culturing of cancer stem cells. PI Steve Quake, Stanford University. These projects are highly interconnected and reliant on each other for the success of the individual project as well as the success of this program. Each project will be supported by 4 cores: an administrative core, a bioinformatics core, an animal model core, and a flow cytometry core.